Principal Investigator/Program Director (Last, first, middle): Furlow, J., David RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 08-24-2006 Animal Welfare Assurance Number A3433-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 8733-ABSTRACT.pdf Mime Type: application/pdf 7. * Project Narrative 5852-narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 1147-references.pdf Mime Type: application/pdf 9. Facilities &Other Resources 1429-Resources.pdf Mime Type: application/pdf 10. Equipment 2389-Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Furlow, J., David Skeletal muscle wasting, or atrophy, is a major human health concern. Immobilization, nerve damage, cachexia, sepsis, and aging induce significant and potentially life-threatening losses in skeletal muscle mass to the point of impairing adequate ambulatory or respiratory function. Adrenal glucocorticoid hormones are potent inducers of skeletal muscle atrophy. Physiological glucocorticoid levels support muscle atrophy in fasting and chronic illness among other catabolic conditions. In addition, synthetic glucocorticoids are used clinically as potent anti-inflammatory drugs with serious side effects such as hyperglycemia, insulin resistance, and bone, cartilage, and muscle loss. New "selective" glucocorticoid receptor ligands have been described that repress inflammatory gene expression but are less potent at up- regulation of other classes of glucocorticoid responsive genes, thus showing good pharmaceutical potential. However, none of these compounds have been evaluated for effects on skeletal muscle. Inhibition of glucocorticoid receptor action selectively in skeletal muscle would present an opportunity to alleviate atrophy under a variety of conditions. In this proposal, we will focus on the role of two recently identified E3 ubiquitin ligase, MuRF1 and MAFbx, in glucocorticoid induced skeletal muscle atrophy, and their transcriptional activation. We propose to 1) determine the relative contribution of MuRF1 and MAFbx genes to glucococorticoid induced skeletal muscle atrophy using mice with selective gene deletions, 2) investigate the role of the glucocorticoid receptor in the induction of muscle atrophy, as well as, MuRF1 and MAFbx expression using mice with a muscle-specific deletion of the glucocorticoid receptor, 3) investigate the role of the glucocorticoid receptor and FOXO proteins in regulating MuRF1 gene expression using chromatin immunoprecipitation assays, and 4) evaluate selective anti-inflammatory glucocorticoid ligands for effects on muscle atrophy and MuRF1 and MAFbx expresssion. Newly developed genetic resources, pharmacological tools, and molecular techniques are available to accomplish these aims in the investigator's laboratories and through